DESCRIPTION OF THE PROGRAM (provided by applicant): Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Phencylidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia, indicating a potentially critical role of NMDA receptors in the etiopathology of primary negative symptoms. NMDA receptors are modulated in vivo by glycine and D-serine, which bind to a modulatory site of the NMDA receptor complex. Clinical trials with NMDA/glycine site agonists have yielded highly encouraging clinical data. This CDDG application will focus on development of D-serine as an effective treatment for persistent negative symptoms and cognitive dysfunction in schizophrenia, in collaboration with Rexim Corporation, a major manufacturer of D-serine and other amino acids for the pharmaceutical industry. The application consists of two projects. Project 1 will consist of PK/PD, dose-finding and subsequent double-blind treatment studies at NKI involving patients, with chronic schizophrenia, and investigating D-serine effects on persistent negative symptoms and cognitive dysfunction. Project 2 will consist of a collaborative multicenter trial of D-serine treatment of the schizophrenia prodrome to be conducted at Yale University and Zucker Hillside Hospital. Together these projects will validate treatment targets for NMDA agonists in general and D-serine in particular and will encourage continued clinical development.